Sites of chronic inflammation are characterized by the presence and activation of multiple types of inflammatory cells, particularly cells of lymphoid lineage (including T lymphocytes) and myeloid lineage (including granulocytes, macrophages and monocytes). Pro-inflammatory mediators, including cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), are produced by these activated cells. Accordingly, an agent which suppresses the activation of these cells or their production of pro-inflammatory cytokines would be useful in the therapeutic treatment of inflammatory diseases or other diseases involving elevated levels of cytokines.
Cyclic AMP (adenosine monophosphate) has been shown to be a second messenger which mediates the biologic responses of cells to a wide range of extracellular stimuli. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated to convert ATP (adenosine triphosphate) to cAMP. The actions of cAMP are terminated by cyclic nucleotide phosphodiesterases (PDEs) which hydrolyze the 3'-phosphodiesterase bond to form 5'-AMP, an inactive metabolite. In short, the intracellular enzyme family of PDEs regulates the level of cAMP in cells. Accordingly, the inhibition of PDE function would prevent the conversion of cAMP to the inactive metabolite 5'-AMP and, consequently, maintain higher cAMP levels (see Beavo and Houslay, Cyclic Nucleotide Phosphodiesterases: Structure, Regulation and Drug Action, Wiley, Chichester, pgs 3-14, 1990).
Elevated levels of cAMP in human myeloid and lymphoid lineage cells are associated with the suppression of cell activation. Type IV cAMP phosphodiesterase (PDE-IV) is a predominant PDE isotype in these cells and is thus a major mechanism of cAMP degradation. It is now recognized that inhibiting PDE-IV function can cause elevation of cAMP in these cells and suppression of cell activation (for review, see Torphy, et al, Novel phosphodiesterase inhibitors for the therapy of asthma, Drug News and Perspectives 6:203-214; Giembycz and Dent, Prospects for selective cyclic nucleotide phosphodiesterase inhibitors in the treatment of bronchial asthma, Clin Exp Allergy 22:337-344).
In particular, PDE-IV inhibitors have been shown to inhibit production of TNF.alpha. and partially inhibit IL-1.beta. release by monocytes (see Semmler, et al, The specific type-IV phosphodiesterase inhibitor rolipram suppresses TNF.alpha. production by human mononuclear cells, Int J Immunopharmacol 15:409-413, 1993; Molnar-Kimber, et al, Differential regulation of TNF-.alpha. and IL-1.beta. production from endotoxin stimulated human monocytes by phosphodiesterase inhibitors, Mediators of Inflammation 1:411-417, 1992). PDE-IV inhibitors have also been shown to inhibit the production of super oxide radicals from human polymorphonuclear leukocytes [see Verghese, et al, J Mol Cell Cardiol 12 (Suppl. II), sS.61; Nielson, et al, Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst, J Allergy Clin Immunol 86:801-808, 1990]; to inhibit the release of vasoactive amines and prostanoids from human basophils (see Peachell, et. al., Preliminary identification and role of phosphodiesterase isozymes in human basophils, J Immunol 148:2503-2510, 1992); to inhibit respiratory bursts in eosinophils (see Dent, et el, Inhibition of eosinophil cyclic nucleotide PDE activity and opsonized zymosan stimulated respiratory burst by type IV-selective PDE inhibitors, Br J Pharmacol 103:1339-1346, 1991); and to inhibit the activation of human T-lymphocytes (see Robicsek, et. al., Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes, Biochem Pharmacol 42:869-877, 1991).
Inflammatory cell activation and excessive or unregulated cytokine (e.g., TNF.alpha. and IL-1.beta.) production are implicated in allergic, autoimmune or inflammatory diseases or disorders, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis, sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shock syndrome, asthma, chronic bronchitis, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, reperfusion injury of the myocardium, brain or extremities, fibrosis, cystic fibrosis, keloid formation, scar formation, atherosclerosis, transplant rejection disorders such as graff vs. host reaction and allograft rejection, chronic granulonephritis, lupus, inflammatory bowel disease such as Crohn's disease and ulcerative colitis and inflammatory dermatoses such as atopic dermatitis, psoriasis or urticaria. Other conditions characterized by elevated cytokine levels include cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), ARC (AIDS related complex), fever and myalgias due to infection, cerebral malaria, osteoporosis and bone resorption diseases, keloid formation, scar tissue formation or pyrexia.
In particular, TNF.alpha. has been implicated in various roles with respect to human acquired immune deficiency syndrome (AIDS). AIDS results from the infection of T-lymphocytes with Human Immunodeficiency Virus (HIV), although HIV also infects and is maintained in myeloid lineage cells. TNF has been shown to upregulate HIV infection in T-lymphocytic and monocytic cells (see Poli, et al, Tumor necrosis factor alpha functions in an autocrine manner in the induction of human immunodeficiency virus expression, Proc Natl Acad Sci 87:782-785, 1990).
Several properties of TNF.alpha. such as stimulation of collagenases, stimulation of anglogenesis in vivo, stimulation of bone resorption and ability to increase the adherence of tumor cells to endothelium are consistent with a role for TNF in the development and metastatic spread of cancer in the host. TNF.alpha. has recently been directly implicated in the promotion of growth and metastasis of tumor cells (see Orosz, et al, Enhancement of experimental metastasis by tumor necrosis factor, J Exp Med 177:1391-1398, 1993).
Accordingly, chemical compounds which selectively inhibit PDE-IV would be useful in the treatment of allergic or inflammatory diseases or other diseases associated with excessive or unregulated production of cytokines, such as TNF. In addition, PDE-IV inhibitors would be useful for treatment of diseases which are associated with elevated cAMP levels or PDE-IV function in a particular target tissue. For example, PDE-IV inhibitors could be used in the treatment of diabetes insipidus (Kidney Int. 37:362, 1990; Kidney Int. 35:494, 1989) and central nervous system disorders, such as depression and multi-infarct dementia (see Eckman, et al, Curr. Ther. Res. 43:291, 1988; Nicholson, Psychopharmacology 101:147, 1990). Another application involving the use of PDE-IV inhibitors concerns modulating bronchodilatory activity via direct action on bronchial smooth muscle cells for the treatment of asthma.